The invention relates to new polycyclic azaindole compounds. The compounds of the present invention are new and have very valuable pharmacological characteristics in respect of melatoninergic receptors.
The prior art describes polycyclic azaindole compounds for use in synthesis (Heterocycles, 41 (9), 1995, pp. 1987-98; Tetrahedron Letters, 26 (10), 1985, pp. 1295-6) or as an tumour and antiviral agents (Tetrahedron, 50 (13), 1994, pp. 3987-92).
Numerous studies in the last ten years have demonstrated the key role of melatonin (N-acetyl-5-methoxytryptamine) in many physiopathological phenomena,and in the control of the circadian rhythm. Its half-like is quite short, however, owing to the fact that it is rapidly metabolised. Great interest therefore lies in the possibility of providing the clinician with melatonin analogues that are metabolically more stable, have an agonist or antagonist character and that may be expected to have a therapeutic effect that is superior to that of the hormone itself.
In addition to their beneficial action on circadian rhythm disorders (J. Neurosurg. 1985, 63, pp. 321-341) and sleep disorders (Psychopharmacology, 1990, 100, pp. 222-226), ligands of the melatoninergic system have valuable pharmacological properties in respect of the central nervous system, especially anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272) and analgesic properties (Pharmacopsychiat., 1987, 20, pp. 222-223) as well as for the treatment of Parkinson""s disease (J. Neurosurg. 1985, 63, pp. 321-341) and Alzheimer""s disease (Brain Research, 1990, 528, pp. 170-174). Those compounds have also demonstrated activity in relation to certain cancers (Melatoninxe2x80x94Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), ovulation (Science 1987, 227, pp. 714-720), diabetes (Clinical Endocrinology, 1986, 24, pp. 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp. 443-446).
Those various effects are exerted via the intermediary of specific melatonin receptors. Molecular biology studies have demonstrated the existence of a number of receptor sub-types that are capable of binding that hormone (Trends Pharmacol. Sci., 1995, 16, p 50 WO 97.04094). It has been possible, for various species, including mammals, for some of those receptors to be located and characterised. In order to be able to understand the physiological functions of those receptors better, it is of great advantage to have available specific ligands. Moreover, such compounds, by interacting selectively with one or other of those receptors, may be excellent medicaments for the clinician in the treatment of pathologies associated with the melatoninergic system, some of which have been mentioned above.
In addition to the fact that the compounds of the present invention are new, they show very strong affinity for melatonin receptors and/or selectivity for one or other of the melatoninergic binding sites.
More especially, the present invention relates to compounds of formula (I): 
wherein:
the symbol 
xe2x80x83represents the grouping 
R1 represents a halogen atom or a group xe2x80x94R, xe2x80x94OR, xe2x80x94S(O)nR, xe2x80x94NRRxe2x80x2, 
or xe2x80x94SO2NRRxe2x80x2 (wherein n is 0, 1 or 2, Z represents a sulphur or oxygen atom, and R, Rxe2x80x2 and Rxe2x80x3, which may be identical or different, represent a hydrogen atom or an unsubstituted or substituted linear or branched (C1-C6)alkyl group, an unsubstituted or substituted linear or branched (C2-C6)alkenyl group, an unsubstituted or substituted linear or branched (C2-C6)alkynyl group, an unsubstituted or substituted (C3-C8)cycloalkyl group, an unsubstituted or substituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a heteroaryl group or a heteroaryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched,
it also being possible for (R and Rxe2x80x2) and (Rxe2x80x2 and Rxe2x80x3) to form together with the nitrogen atom carrying them a morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl group, those groups being unsubstituted or substituted),
G1 represents an alkylene chain having from 1 to 4 carbon atoms, optionally substituted by a group R, OR, COR or COOR (wherein R is as defined hereinbefore),
or G1 represents an alkylene chain having from 1 to 4 carbon atoms in which one of CH2 group can be replaced by a cycloalkylene(C3-C8) group,
A represents a group 
wherein R, Rxe2x80x2, Rxe2x80x3 and Z are as defined hereinbefore,
B forms with the nitrogen atom and the carbon atom to which it is attached a ring having from 5 to 8 ring members, which may contain one or more unsaturated bonds and may contain, in addition to the nitrogen atom, an additional hetero atom selected from oxygen, sulphur and nitrogen,
R2 and R3, which may be identical or different, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group or a hydroxy group,
or R2 and R3 together form an oxo group,
R4 and R5 represent a hydrogen atom or form together with two adjacent atoms of the B ring carrying them a group selected from aryl and heteroaryl,
the symbol ----- means that the bond may be single or double, with the proviso that the valence of the atoms is respected,
it being understood that:
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d, xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9cmorpholinylxe2x80x9d, xe2x80x9cpiperidinylxe2x80x9d, xe2x80x9cpiperazinylxe2x80x9d and xe2x80x9cpyrrolidinylxe2x80x9d means that those groups may be substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
the term xe2x80x9csubstitutedxe2x80x9d applied to the term xe2x80x9ccycloalkylalkylxe2x80x9d means that the cyclic moiety of the group is substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
xe2x80x9carylxe2x80x9d is understood to mean a phenyl, naphthyl or biphenyl group, those groups being unsubstituted or substituted by one or more identical or different: groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, alkoxycarbonyl, amido, and halogen atoms,
xe2x80x9cheteroarylxe2x80x9d is understood to mean a furyl, pyrrolyl, imidazolyl, pyridyl, thienyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, quinolyl or quinazolinyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, amido, and halogen atoms,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
An advantageous variant of the present invention relates to compounds of formula (I): 
wherein:
the symbol 
xe2x80x83represents the grouping 
R1 represents a halogen atom or a group xe2x80x94R, xe2x80x94OR, xe2x80x94S(O)nR, xe2x80x94NRRxe2x80x2, 
or xe2x80x94SO2NRRxe2x80x2 (wherein n is 0, 1 or 2, Z represents a sulphur or oxygen atom, and R, Rxe2x80x2 and Rxe2x80x3, which may be identical or different, represent a hydrogen atom or an unsubstituted or substituted linear or branched (C1-C6)alkyl group, an unsubstituted or substituted linear or branched (C2-C6)alkenyl group, an unsubstituted or substituted linear or branched (C2-C6)alkynyl group, an unsubstituted or substituted (C3-C8)cycloalkyl group, an unsubstituted or substituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a heteroaryl group or a heteroaryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched,
it also being possible for (R and Rxe2x80x2) and (Rxe2x80x2 and Rxe2x80x3) to form together with the nitrogen atom carrying them a morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl group, those groups being unsubstituted or substituted),
G1 represents an alkylene chain having from 1 to 4 carbon atoms, optionally substituted by a group R, OR, COR or COOR (wherein R is as defined hereinbefore),
A represents a group 
wherein R, Rxe2x80x2, Rxe2x80x3 and Z are as defined hereinbefore,
B forms with the nitrogen atom and the carbon atom to which it is attached a ring having from 5 to 8 ring members, which may contain one or more unsaturated bonds and may contain, in addition to the nitrogen atom, an additional hetero atom selected from oxygen, sulphur and nitrogen,
R2 and R3, which may be identical or different, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group or a hydroxy group,
or R2 and R3 together form an oxo group,
R4 and R5 represent a hydrogen atom or form together with two adjacent atoms of the B ring carrying them a group selected from aryl and heteroaryl,
the symbol ----- means that the bond may be single or double, with the proviso that the valence of the atoms is respected,
it being understood that:
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d, xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9cmorpholinylxe2x80x9d, xe2x80x9cpiperidinylxe2x80x9d, xe2x80x9cpiperazinylxe2x80x9d and xe2x80x9cpyrrolidinylxe2x80x9d means that those groups may be substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
the term xe2x80x9csubstitutedxe2x80x9d applied to the term xe2x80x9ccycloalkylalkylxe2x80x9d means that the cyclic moiety of the group is substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
xe2x80x9carylxe2x80x9d is understood to mean a phenyl, naphthyl or biphenyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, alkoxycarbonyl, amido, and halogen atoms,
xe2x80x9cheteroarylxe2x80x9d is understood to mean a furyl, pyrrolyl, imidazollyl, pyridyl, thienyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, quinolyl or quinazolinyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, amido, and halogen atoms,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
An another advantageous variant of the present invention relates to compounds of formula (I): 
wherein:
the symbol 
xe2x80x83represents the grouping 
R1 represents a halogen atom or a group xe2x80x94R, xe2x80x94OR, xe2x80x94S(O)nR, xe2x80x94NRRxe2x80x2, 
or xe2x80x94SO2NRRxe2x80x2 (wherein n is 0, 1 or 2, Z represents a sulphur or oxygen atom, and R, Rxe2x80x2 and Rxe2x80x3, which may be identical or different, represent a hydrogen atom or an unsubstituted or substituted linear or branched (C1-C6)alkyl group, an unsubstituted or substituted linear or branched (C2-C6)alkenyl group, an unsubstituted or substituted linear or branched (C2-C6)alkynyl group, an unsubstituted or substituted (C3-C8)cycloalkyl group an unsubstituted or substituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a heteroaryl group or a heteroaryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched,
it also being possible for (R and Rxe2x80x2) and (Rxe2x80x2 and Rxe2x80x3) to form together with the nitrogen atom carrying them a morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl group, those groups being unsubstituted or substituted),
G1 represents an alkylene chain having from 1 to 4 carbon atoms in which one of CH2 group can be replace cycloalkylene (C3-C8) group,
A represents a group 
wherein R, Rxe2x80x2, Rxe2x80x3 and Z are as defined hereinbefore,
B forms with the nitrogen atom and the carbon atom to which it is attached a ring having from 5 to 8 ring members, which may contain one or more unsaturated bonds and may contain, in addition to the nitrogen atom, an additional hetero atom selected from oxygen, sulphur and nitrogen,
R2 and R3, which may be identical or different, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group or a hydroxy group,
or R2 and R3 together form an oxo group,
R4 and R5 represent a hydrogen atom or form together with two adjacent atoms of the B ring carrying them a group selected from aryl and heteroaryl,
the symbol ----- means that the bond may be single or double, with the proviso that the valence of the atoms is respected,
it being understood that:
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d, xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9cmorpholinylxe2x80x9d, xe2x80x9cpiperidinylxe2x80x9d, xe2x80x9cpiperazinylxe2x80x9d and xe2x80x9cpyrrolidinylxe2x80x9d means that those groups may be substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
the term xe2x80x9csubstitutedxe2x80x9d applied to the term xe2x80x9ccycloalkylalkylxe2x80x9d means that the cyclic moiety of the group is substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
xe2x80x9carylxe2x80x9d is understood to mean a phenyl, naphthyl or biphenyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, alkoxycarbonyl, amido, and halogen atoms,
xe2x80x9cheteroarylxe2x80x9d is understood to mean a furyl, pyrrolyl, imidazolyl, pyridyl, thienyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, quinolyl or quinazolinyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, amido, and halogen atoms,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylaniine, tert-butylamine, etc.
The preferred compounds of the invention are the compounds of formula (I) wherein B forms with the nitrogen atom and the carbon atom to which it is attached a pyrrolidine ring, a piperidine ring, a (perhydro)azepine ring (7 ring members), a (perhydro)azocine ring (8 ring members) or a ring containing in addition to the nitrogen atom an oxygen atom, and more preferably a 1,3-(perhydro)oxazine ring.
The preferred groups R2 and R3 of the compounds of formula (I) are the hydrogen atom.
The preferred groups R4 and R5 of the compounds of formula (I) are the hydrogen atom or when R4 and R5, carried by two adjacent atoms of the B ring, form with those two atoms an unsubstituted or substituted phenyl group.
The invention relates more especially to the compounds of formula (I) wherein R1 represents a group OR and more preferably a group OR wherein R represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or tert-butyl.
The preferred group G1 of the compounds of formula (I) is the group (CH2)p wherein p is 2 or 3 and more preferably 2.
Advantageously, the invention relates to compounds of formula (I) wherein A represents a group NHCOR or CONHR and more especially a group NHCOR or CONHR wherein R represents a linear or branched (C1-C6)alkyl group, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or tert-butyl, a (C3-C8)cycloalkyl group, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, a (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, such as, for example, cyclopropylmethyl, cyclobutylmethyl or cyclohexylmethyl, an aryl group, such as, for example, phenyl, iodophenyl, trifluoromethylphenyl or methoxyphenyl, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, such as, for example, benzyl, or a heteroaryl group, such as, for example, furyl, thienyl, pyrrolyl, pyridyl or indolyl.
The invention relates most especially to the compounds of formula (I) that are
N-[2-(2-methoxy-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-11-yl)ethyl]acetamide,
N-[2-(2-methoxy-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-1-yl)ethyl]-2-furamide,
N-[2-(2-methoxy-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-11-yl)ethyl]benzamide,
N-[2-(3-methoxy-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl)ethyl]acetamide,
N-[2-(2-methoxy-6,7,8,9-tetrahydropyrido[2,3-b]indolizin-10-yl)ethyl]-2-furamide,
N-[2-(2-methoxy-6,7,8,9-tetrahydropyrido[2,3-b]indolizin-10-yl)ethyl]acetamide,
N-[2-(8-methoxy-3,4-dihydro-2H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-b][1,3]oxazin-10-yl)ethyl]acetamide,
N-[2-(8-methoxy-3,4-dihydro-2H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-b][1,3]oxazin-10-yl)ethyl]-2-furamide,
N-[2-(10-methoxy-5 ,6-dihydropyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoquinolin-12-yl)ethyl]-2-furamide,
N-[2-(11-methoxy-6,7-dihydro-5H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a][2]benzazepin-13-yl)ethyl]acetamide,
N-[2-(11-methoxy-6,7-dihydro-5H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a][2]benzazepin-13-yl)ethyl]-2-furamide,
N-[2-(11-hydroxy-6,7-dihydro-5H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a][2]benzazepin-13-yl)ethyl]-2-furamide.
The enantiomers, diastereoisomers and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): 
wherein W represents a radical of formula (III): 
wherein R1, R2, R3, R4, R5, B, the symbol 
and the symbol ---- are as defined hereinbefore,
which is subjected to
the action of a reducing agent to obtain a compound of formula (IV):
Wxe2x80x94CH2OHxe2x80x83xe2x80x83(IV)
wherein W is as defined hereinbefore,
which, after conversion to the corresponding halogen compound, is subjected to the action of a cyanide salt to yield a compound of formula (V):
Wxe2x80x94CH2xe2x80x94CNxe2x80x83xe2x80x83(V)
wherein W is as defined hereinbefore,
or, in succession, a Wittig reaction and then reduction to obtain a compound of formula (VI):
Wxe2x80x94Gxe2x80x21xe2x80x94Xxe2x80x83xe2x80x83(VI)
wherein W is as defined hereinbefore, X represents a group CN or COOalk (wherein alk represents an alkyl group) and Gxe2x80x21 represents a chain as defined hereinbefore for G1 having from 2 to 4 carbon atoms,
which compounds of formulae (V) and (VI) are hydrolysed in an acidic or basic medium to obtain a compound of formula (VII):
Wxe2x80x94G1xe2x80x94COOHxe2x80x83xe2x80x83(VII)
wherein W and G1 are as defined hereinbefore,
which is subjected, in the presence of a coupling agent or after conversion to the corresponding acid chloride, to the action of an amine HNRRxe2x80x2 wherein R and Rxe2x80x2 are as defined hereinbefore to yield a compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein W, G1, R and Rxe2x80x2 are as defined hereinbefore, which compound of formula (I/a), when R and Rxe2x80x2 simultaneously represent a hydrogen atom, is subjected to the action of NaOBr to yield, after hydrolysis, a compound of formula (VIII):
Wxe2x80x94G1xe2x80x94NH2xe2x80x83xe2x80x83(VIII)
wherein W and G1 are as defined hereinbefore,
which is subjected to the action of:
an acyl chloride of formula (IX): 
wherein R is as defined hereinbefore, or the corresponding acid anhydride (mixed or symmetric),
to obtain a compound of formula (I/b), a particular case of the compounds of formula (I): 
wherein W, G1 and R are as defined hereinbefore,
which compound of formula (I/b) may also be obtained, when G1 represents a chain (CH2)2, starting from a compound of formula (II) by the action of nitromethane to yield a compound of formula (IIIxe2x80x2): 
wherein W is as defined hereinbefore,
which is subjected to the action of a reducing agent, such as NaBH4, for example, to obtain a compound of formula (IVxe2x80x2): 
wherein W is as defined hereinbefore,
which is subjected to catalytic hydrogenation to obtain a compound of formula (Vxe2x80x2): 
wherein W is as defined hereinbefore,
which is subjected to the action of an acid chloride of formula (IX) or the corresponding acid anhydride (mixed or symmetric) to obtain a compound of formula (I/bxe2x80x2), a particular case of the compounds of formula (I/b): 
wherein W and R are as defined hereinbefore,
or which compound of formula (VIII) is subjected to the action of a compound of formula (X):
Oxe2x95x90Cxe2x95x90Nxe2x80x94Rxe2x80x83xe2x80x83(X)
wherein R is as defined hereinbefore,
to yield a compound of formula (I/c), a particular case of the compounds of formula (I): 
wherein W, G1 and R are as defined hereinbefore,
which compounds of formulae (I/b) and (I/c) may be subjected to the action of a compound of formula (XI):
Raxe2x80x94Jxe2x80x83xe2x80x83(XI)
wherein Ra can have any of the meanings of R with the exception of the hydrogen atom and J represents a leaving group, such as a halogen atom or a tosyl group,
to yield a compound of formula (I/d), a particular case of the compounds of formula (I): 
wherein W, G1 and Ra are as defined hereinbefore and Y represents a group R or xe2x80x94NRRxe2x80x2 wherein R and Rxe2x80x2 are as defined hereinbefore,
and/or which compounds of formulae (I/a), (I/b), (I/c) and (I/d) may be subjected to the action of a thionisation agent, such as Lawesson""s reagent, to yield a compound of formula (I/e), a particular case of the compounds of formula (I):
Wxe2x80x94G1xe2x80x94Txe2x80x83xe2x80x83(I/e)
wherein W and G1 are as defined hereinbefore and T represents a group 
xe2x80x83wherein R, Rxe2x80x2 and Y are as defined hereinbefore,
which compounds (I/a) to (I/e) constitute the totality of the compounds of formula (I) and may be purified according to a conventional purification technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and separated, where appropriate, into their isomers according to a conventional separation technique.
The compounds of formula (III) are either commercial products or are accessible to the person skilled in the art by conventional chemical reactions.
In particular, the compounds of formula (III) may be obtained starting from a compound of formula (XII): 
wherein R1 and the symbol 
are as defined hereinbefore,
which is either a commercial product or is obtained according to a procedure described by G. Guillaumet et al. (Heterocycles, 1999, 50 (2), pp. 1065-1079),
which is condensed with a compound of formula (XIII):
Halxe2x80x94G2xe2x80x94Halxe2x80x83xe2x80x83(XIII)
wherein Hal represents a halogen atom and G2 represents a chain containing from 3 to 6 ring members, substituted by the groups R2, R3, R4 and R5 as defined hereinbefore, that may contain one or more unsaturated bonds and optionally contains a hetero atom selected from oxygen, nitrogen and sulphur,
to yield a compound of formula (XIV): 
wherein R1, G2, Hal and the symbol 
are as defined hereinbefore,
which is converted, by the successive action of bromine in tBuOH and then zinc in acetic acid, to a compound of formula (XV): 
wherein R1, G2, Hal and the symbol 
xe2x80x83are as defined hereinbefore,
or formylated by the action of POCl3 in dimethylformamide (DMF) to yield a compound of formula (XVI): 
wherein R1, G2, Hal and the symbol 
xe2x80x83are as defined hereinbefore,
(it also being possible for the compound of formula (XVI) to be obtained starting from a compound of formula (XII), which is subjected in succession to formulation and then to condensation of the compound of formula (XIII)),
which compound of formula (XVI) is placed in cyclisation conditions, such as Bu3SnH/AIBN, to yield a compound of formula (III),
which compounds of formulae (XIV) and (XV) may also be subjected to cyclisation conditions using, depending upon the case, reagents such as, for example, NaH in DMF or (PPh3)4Pd, to yield a compound of formula (XVII): 
wherein R1, R2, R3, R4, R5, B and the symbol 
xe2x80x83are as defined hereinbefore,
which is subjected to formylation conditions, such as POCl3 in DMF, to obtain a compound of formula (III).
The present invention relates also to compounds of formula (XVII) as defined hereinbefore for use as intermediates in the synthesis of compounds of formula (I).
The compounds of the invention and the pharmaceutical compositions containing them have proved to be useful in the treatment of disorders of the melatoninergic system.
Pharmacological study of the compounds of the invention has in fact shown that they are atoxic, have a very high affinity for melatonin receptors and have substantial activities in respect of the central nervous system, and, in particular, therapeutic properties in respect of sleep disorders, anxiolytic, antipsychotic and analgesic properties, as well as properties in respect of microcirculation have been found, enabling it to be established that the compounds of the invention are useful in the treatment of stress, sleep disorders, anxiety. seasonal affective disorder, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson""s disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, Alzheimer""s disease, and in cerebral circulation disorders. In another field of activity, it appears that the compounds of the invention can be used in the treatment of sexual dysfunctions, that they have ovulation-inhibiting and immunomodulating properties and are capable of being used in the treatment of cancers.
The compounds will preferably be used in the treatment of seasonal affective disorder, sleep disorders, cardiovascular pathologies, insomnia and fatigue due to jetlag, appetite disorders and obesity.
For example, the compounds will be used in the treatment of seasonal affective disorder and sleep disorders.
The present invention relates also to pharmaceutical compositions comprising at least one compound of formula (I) on its own or in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration and especially tablets or dragxc3xa9es, sublingual tablets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication or any associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in one or more administrations.